„Weiche” und „harte” Endpunkte am Beispiel der Hypertonie

Zusammenfassung

Hypertonie ist ein Risikofaktor mit langer Latenz. Davon betroffene Patienten sterben unbehandelt im Mittel einige Jahre früher als die altersentsprechende Gesamtbevölkerung. Die Hypertonie-Interventionsstudien der ersten Phase belegten im Plazebovergleich den Nutzen einer antihypertensiven Therapie bezüglich harter Endpunkte von zweifelsfreier klinischer Relevanz (Mortalität, Schlaganfall, Myokardinfarkt). In einer zweiten Phase der Hypertonie-Interventionsstudien, die bis in die Gegenwart reicht, werden aktive Behandlungsstrategien miteinander verglichen. Das Problem in dieser Phase besteht darin, dass bei den harten Endpunkten kleinere Unterschiede als in plazebokontrollierten Studien zu erwarten sind. Daher werden nun Zeichen der Organschädigung, die zwischen der Diagnose des hohen Blutdrucks und den harten Endpunkten auftreten (z. B. linksventrikuläre Hypertrophie, Mikroalbuminurie, Intima-Media-Dikke) als zusätzliche Endpunkte untersucht. Diese Intermediär- oder Surrogatendpunkte sind nach epidemiologischen Daten mehr oder weniger prädiktiv für harte Endpunkte. Durch systematisches Inkludieren solcher Surrogate in große Studien wird seit einigen Jahren versucht, die prädiktive Wertigkeit dieser Parameter zu erhöhen. Zu den patientenrelevanten Effekten einer antihypertensiven Therapie gehört auch ein neu aufgetretener Diabetes mellitus.

Summary

Hypertension is a disease with a long latency. Those afflicted will, if untreated, die earlier than an age-matched cohort within the general population. In a first phase of intervention trials it was demonstrated that anti-hypertensive treatment, in comparison with placebo, results in a reduction of so-called hard end points (death, stroke, myocardial infarction). In a second phase of clinical trials, which is still continuing, active treatment strategies are being compared. The problem in this phase is that differences in these hard end points are smaller than in placebo-controlled trials. For this reason signs of organ damage that occur in the time between the diagnosis of high blood pressure and the occurrence of hard end points (e.g. left ventricular hypertrophy, microalbuminuria, intima/media thickness) are used as additional end points. According to epidemiological data, these intermediate or surrogate end points are more or less predictive of hard end points. Systematic inclusion of such surrogates in large trials has been tried for some years in an attempt to raise the predictive power of these parameters. Another patient-relevant endpoint of antihypertensive treatment is the new occurrence of diabetes mellitus..

Literatur

• 1 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group . The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).  JAMA. 2002;  288 2981-2997
• 2 Bosch J, Lonn E, Pogue J, Arnold J M, Dagenais G R, Yusuf S. HOPE/HOPE-TOO Study Investigators . Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension.  Circulation. 2005;  112 1339-1346
• 3 Brown M J, Palmer C R, Castaigne A. et al . Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).  Lancet. 2000;  356 366-372
• 4 Budoff M J, Cohen M C, Garcia M J. et al. American College of Cardiology Foundation; American Heart Association; American College of Physicians Task Force on Clinical Competence; American Society of Echocardiography; American Society of Nuclear Cardiology; Society of Atherosclerosis Imaging; Society for Cardiovascular Angiography & Interventions; Society of Cardiovascular Computed Tomography . ACCF/AHA clinical competence statement on cardiac imaging with computed tomography and magnetic resonance.  Circulation. 2005;  112 598-617
• 5 Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease.  Br Med Bull. 1994;  50 272-298
• 6 Collins R, Peto R, MacMahon S. et al . Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context.  Lancet. 1990;  335 827-838
• 7 Dahlöf B, Devereux R B, Kjeldsen S E. et al.; LIFE Study Group . Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.  Lancet. 2002;  359 995-1003
• 8 Dahlöf B, Sever P S, Poulter N R. et al.; ASCOT Investigators . Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.  Lancet. 2005;  366 895-906
• 9 Hillege H L, Fidler V, Diercks G F. et al.; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group . Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.  Circulation. 2002;  106 1777-1782
• 10 Ibsen H, Olsen M H, Wachtell K. et al . Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.  Hypertension. 2005;  45 198-202
• 11 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration . Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.  Lancet. 2002;  360 1903-1913
• 12 Liu L, Wang J G, Gong L, Liu G, Staessen J A. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Systolic Hypertension in China (Syst-China) Collaborative Group.  J Hypertens. 1998;  16 1823-1829
• 13 Motro M, Shemesh J. Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics.  Hypertension. 2001;  37 1410-1413
• 14 O’Leary D H, Polak J F, Kronmal R A, Manolio T A, Burke G L, Wolfson S K. Cardiovascular Health Study Collaborative Research Group . Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults.  N Engl J Med. 1999;  340 14-22
• 15 SHEP Cooperative Research Group . Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP).  JAMA. 1991;  265 3255-3264
• 16 Staessen J A, Fagard R, Thijs L. et al. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators . Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.  Lancet. 1997;  350 757-764
• 17 Staessen J A, Gasowski J, Wang J G. et al . Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials.  Lancet. 2000;  355 865-872
• 18 Wachtell K, Lehto M, Gerdts E. et al . Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study.  J Am Coll Cardiol. 2005;  45 712-719
• 19 Yusuf S, Gerstein H, Hoogwerf B. et al.; HOPE Study Investigators . Ramipril and the development of diabetes.  JAMA. 2001;  286 1882-1885
• 20 Zanchetti A, Bond M G, Hennig M. et al.; European Lacidipine Study on Atherosclerosis investigators . Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial.  Circulation. 2002;  106 2422-2427